The candidate for this Mentored Clinical Scientist Research Career Development Award is John Chorba, MD, an Assistant Adjunct Professor (Medicine/Cardiology) at the San Francisco General Hospital and University of California, San Francisco. The primary goal of this award is for the candidate to obtain the training and skills necessary to become a successful independent physician-scientist at an academic medical center. Dr. Chorba's research objective is to use a chemical biology approach in investigating the role of the proprotein convertase subtilisin-kexin type 9 (PCSK9) active site in modulating PCSK9 processing. His long- term career goal is to use chemical tools to understand the molecular mechanisms underlying hypercholesterolemia, lipid metabolism, and the development of atherosclerosis for the purpose of developing novel therapies for heart disease. The training plan involves primary mentorship under Prof. Kevan Shokat, a world-class investigator and expert in developing chemical tools to probe biological questions. Additional guidance will be provided by an impressive group of experts who are leaders in protease biochemistry (Prof. Charles Craik, UCSF), vascular and lipid biology (Profs. Peter Ganz and John Kane, UCSF), cellular trafficking (Prof. David Ginsburg, U. of Michigan), and human genetics (Prof. Helen Hobbs, UT Southwestern). The research facilities and equipment at the institution, UCSF, are outstanding. The training plan also includes focused tutorials and didactic coursework in chemical biology, organic chemistry, structural biology, and lipid biology, as well as participatio and presentation at conferences and mentored guidance with manuscript and grant preparation. As PCSK9 acts to degrade the low-density lipoprotein (LDL) receptor, the major source of clearance of pro-atherogenic LDL cholesterol from the bloodstream, this project has direct implications for the understanding and treatment of atherosclerosis. Specifically, Aim 1 investigates the role of the PCSK9 active site in the generality and specificity of PCSK9 proteolysis, using parallel in vitro and cell culture approaches. Aim 2 investigates the impact of the active site on PCSK9 secretion and LDL-R expression, using an experimental system that bypasses the need for proteolysis in PCSK9 processing. In aim 3, the application proposes to develop chemical probes to dissect PCSK9 proteolysis from secretion and determine the structural requirements of each of these functions, and ultimately serve as starting points for novel therapeutics. Dr. Chorba's Career Development Award proposal comprises a promising candidate, outstanding training environment, rigorous training plan, and an exciting research proposal utilizing new methodologies, all with a direct relevance to human health and disease. At the completion of this Award, Dr. Chorba will have the skills necessary to succeed as an independent investigator.